Leukemias Flashcards
What is meant by Leukemias?
Cancer of white blood cells - unregulated proliferation of immature blood cells.
Why does unregulated proliferation of immature WBC cause death?
‘squeezes out’ normal functional cells and so leads to immunosuppresion
What is meant by acute and chronic phase?
Chronic phase - usually long, involved in the initiation of cancer and loosely linked with the benign phase. Patients can survive for a long time in the chronic phase.
Acute phase - is triggered suddenly and treatment is needed urgently.
Outline the clinical presentation of chronic myeloid leukemia (CML)
Fatigue, anaemia, splenomegaly (enlarged spleen), hepatomegaly (enlarged liver), elevated no. of WBCs.
Outline the three phases of CML
- Initial chronic phase
- Accelerated phase - seen in 2/3 of people, others skip this.
- Acute leukemic phase - blast crisis. Lasts 3-6 months and inevitably leads to death.
Discuss the aetiology of leukemias
Leukamogenesis - multifactorial process, accumulation of mutations.
Ras is mutated in 50% of AML.
Chromosomal abnormalities are common
Novel oncogenes associated (Bcr-Abl) 95% of CMLs have reciprocal translocation between chromosomes 9 and 22.
What is the philladephia chromosome? how does this cause CML?
Fusion between breakpoint cluster region (BCR) on chromsome 22 and Abl tyrosine kinase (c-Abl) on chromosome 9.
BCL-2 is an antiapoptotic protein and moves from a region of low expression next to the Ig receptor which is transcribed at a much higher rate.
The Philadelphia chromosome results from a reciprocal translocation of sections of chromosomes 9 and 22.
How does the BCR-Abl oncoprotein result in CML?
Has elevated tyrosine kinase activity and so drives proliferation via signaling pathways. Many pathways become constitutively activated:
Ras pathway (cell growth)
PI3K (cell survival)
STATS
what is glivec (imatinib)?
Small molecule inhibitor of ATP binding site of Abl tyrosine kinase in its INACTIVE form. blocks the recruitment of ATP and therefore the phosphorylation of downstream substrates.
Glivec is fairly specific, however does block some other tyrosine kinases. What are these? How could this be beneficial?
Also blocks PDGFbR and c-kit tyrosine kinases.
Platelet-derived growth factor receptor kinase is involved in another type of leukemia = CMML.
C-kit is dysregulated in GIST cancers.
How is Glivec given? How do the doses of Glivec vary depending on the phase the patient is in?
Given orally, once daily.
400mg daily in chronic phase and 600mg/day in the accelerate and blast crisis phase.
How can resistance to Glivec arise?
- Point mutations in the ATP binding site preventing Glivec binding
- Amplification of the BCR-ABL - more is produced and so have to keep on givign more glivec to overcome this
What examples of 2nd and 3rd generation therapies for CML exist when Glivec resistance occurs?
Dasatinib and nilotinib bind activate confirmation of BRC-Abl and therefore can be effective in patients in which a point mutation has led to resistance.
However neither therapies are effective against the T3151 mutation.
What is Dasatinib? When is it used?
Orally activite small molecule inhibitor of Src.
Used in the treatment of CML for people who have already tried over treatments.
CML 100mg OD
What is Nilotinib?
Orally active inhibitor of BCR-ABL?
Inhibits 32 out of 33 of the BCR-ABL mutants that are resistant to imatinib (but not T3151)
